HIV CO-RECEPTORS IN THE CNS

Release Date:  January 29, 1999

PA NUMBER:  PA-99-056

P.T.

National Institute of Mental Health
National Institute on Drug Abuse
National Institute of Neurological Disorders and Stroke

PURPOSE

The purpose of this initiative is to stimulate research to increase
understanding of the role of fusin co-factors in HIV infection of the CNS and
to identify and develop analogs and related compounds of these co-factors as
potential therapeutic agents.

Recent evidence indicates that several members of the chemokine receptor
family act as co-receptors for HIV infection.  These distinct molecules show
specific cytotropisms for different HIV isolates. This raises questions about
transmission and pathogenesis, and identifies new potential targets for
therapeutic intervention.  The primary infected cell within the CNS is the
microglia, although a low level of infection of astrocytes is evident. HIV
infection of microglia is CD4-dependent, and occurs primarily with macrophage
tropic HIV isolates.  However, infection of astrocytes as well as other
neural-derived cells is CD4-independent.  Interaction of specific regions of
HIV envelope with cells in the CNS may be responsible for the development of
HIV-associated dementia in some infected individuals, although specific
determinants mediating this dementia have not been identified. It also has
been demonstrated that opioids interact with chemokines indirectly, possibly
through interactions at the level of opioid and chemokine receptors.  This is
a likely mechanism for the observed effects of opioids on the growth of HIV
within microglia within the brain.

This Program Announcement solicits research on co-factors involved in HIV
infection of cells within the CNS, what role these co-factors may play in
disease pathogenesis, and how they may serve as targets for therapeutic
interventions.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2000," a PHS led national
activity for setting priority areas.  This Program Announcement (PA), HIV Co-
Receptors in the CNS is related to the priority area of HIV infection. 
Potential applicants may obtain a copy of "Healthy People 2000" at
http://www.crisny.org/health/us/health7.html

ELIGIBILITY REQUIREMENTS

Applications may be submitted by foreign and domestic, for-profit and non-
profit organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of State and local governments, and eligible
agencies of the Federal government. Racial/ethnic minority individuals, women,
and persons with disabilities are encouraged to apply as Principal
Investigators.

MECHANISM OF SUPPORT

Mechanisms that will be supported by this initiative are research project
grants (R01) and program projects (P01).  Because program projects grants
(P01) have special application formats, and review criteria, applicants are
strongly encouraged to consult with program staff (listed under INQUIRIES) and
to obtain the appropriate additional announcements for those grant mechanisms.

RESEARCH OBJECTIVES

Summary

It is well established that HIV invades the CNS, frequently within weeks of
infection.  Neurons are not infected, but rather productive infection of the
brain occurs primarily via blood-derived macrophages and resident microglia.
Recent evidence indicates that several members of the chemokine receptor
family are used as co-receptors for HIV infection.  These distinct molecules
show specific cytotropisms for different HIV isolates. This raises questions
about transmission and pathogenesis, and identifies new potential targets for
therapeutic intervention.

The primary infected cell within the CNS is the microglia, although a low
level of infection of astrocytes is evident. HIV infection of microglia is
CD4-dependent, and occurs primarily with macrophage tropic HIV isolates. 
However, infection of astrocytes as well as other neural-derived cells is CD4-
independent.  Interaction of specific regions of HIV envelope with cells in
the CNS may be responsible for the development of HIV-associated dementia in
some infected individuals, although specific determinants mediating this
dementia have not been identified. Normal neuronal function requires the
interaction of the neuron with the glial cells within its environment, much of
which is mediated through cytokine/receptors interactions.  The use of these
receptors by HIV may interrupt this delicate balance of cellular
communication. 

Research solicited by this Program Announcement include, but are not limited
to, the following topics:

o  the identification of co-receptors that are expressed in the CNS and on the
cell types on which they are expressed,

o  the primary HIV-1 strains that can be cultured and typed from the CNS and
whether these strains use chemokine or other co-receptors,

o  the mechanism by which chemokine, drugs, or other co-receptors contribute
to HIV infectivity of CD4 negative CNS cell types,

o  the function of chemokine receptors in the CNS under control conditions,
and how their use by HIV impacts on this function,

o  how co-receptors contribute to viral tropisms switching,

o  which chemokine receptors expressed by microglia and astrocytes in vitro
act as receptors for HIV, and whether they are sufficient or necessary,
whether they work in concert with other molecules that bind HIV or are, in
fact, co-receptors,

o  how chemokine/receptor interactions may be disrupted in other CNS
inflammatory conditions,

o  the qualitative or quantitative differences in the expression of these
molecules in different areas of the inflamed CNS,

o  the relationship between the expression of these molecules and pathology in
the HIV-infected brain,

o  the level of constitutive expression of these co-receptors and the
magnitude of induction by HIV infection, 

o  which cells within the CNS express these molecules,

o  how binding of the virus to the co-receptors disturbs or alters signal
transduction pathways,

o  mechanisms related to chemokine and other receptor modulation of HIV entry
and growth and successive alteration of neural function, and

o  chemokine regulation of HIV entry, modulation of such actions by co-factors
and sequential neural impairment.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and
their subpopulations must be included in all NIH supported biomedical and
behavioral research projects involving human subjects, unless a clear and
compelling rationale and justification is provided that inclusion is
inappropriate with respect to the health of the subjects or the purpose of the
research.  This policy results from the NIH Revitalization Act of 1993
(Section 492B of Public Law 103-43).

All investigators proposing research involving human subjects should read the
"NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical
Research," which have been published in the Federal Register of March 28, 1994
(FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23,
No. 11, March 18, 1994 available on the web at the following URL address: 
http://www.nih.gov/grants/guide/notice-files/not94-105.html

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them. 
This policy applies to all initial (Type 1) applications submitted for receipt
dates after October 1, 1998.

All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjects" that was published in the NIH Guide for
Grants and Contracts, March 6, 1998, and is available at the following URL
address: http://www.nih.gov/grants/guide/notice-files/not98-024.html

Investigators also may obtain copies of these policies from the program staff
listed under INQUIRIES.  Program staff may also provide additional relevant
information concerning the policy.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev.
4/98) and will be accepted at the standard application deadlines as indicated
in the application kit.  Application kits are available at most institutional
offices of sponsored research and may be obtained from the Division of
Extramural Outreach and Information Resources, National Institutes of Health,
6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 435-
0714, fax: (301) 480-0525 Email: GrantsInfo@NIH.GOV.  The title and number of
the program announcement must be typed in Section 2 on the face page of the
application.

Applicants planning to submit an investigator-initiated new (type 1),
competing continuation (type 2), competing supplement, or any amended/revised
version of the preceding grant application types requesting $500,000 or more
in direct costs for any year are advised that he or she must contact the
Institute or Center (IC) program staff before submitting the application,
i.e., as plans for the study are being developed.  Furthermore, the
application must obtain agreement from the IC staff that the IC will accept
the application for consideration for award.  Finally, the applicant must
identify, in a cover letter sent with the application, the staff member and
Institute or Center who agreed to accept assignment of the application.

This policy requires an applicant to obtain agreement for acceptance of both
any such application and any such subsequent amendment.  Refer to the NIH
Guide for Grants and Contracts, March 20, 1998 at 
http://www.nih.gov/grants/guide/notice-files/not98-030.html

The completed original application and five legible copies must be sent or
delivered to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established PHS referral
guidelines.  Applications that are complete will be evaluated for scientific
and technical merit by an appropriate peer review group convened in accordance
with the standard NIH peer review procedures.  As part of the initial merit
review, all applications will receive a written critique and undergo a process
in which only those applications deemed to have the highest scientific merit,
generally the top half of applications under review, will be discussed,
assigned a priority score, and receive a second level review by the
appropriate national advisory council or board, when applicable.

Review Criteria

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health. In the
written comments reviewers will be asked to discuss the following  aspects of
the application in order to judge the likelihood that the  proposed research
will have a substantial impact on the pursuit of these goals. Each of these
criteria will be addressed and considered in assigning the overall score,
weighting them as appropriate for each application. Note that the application
does not need to be strong in all categories to be judged likely to have major
scientific impact and thus deserve a high priority score. For example, an
investigator may propose to carry out important work that by its nature is not
innovative but is essential to move a field forward.

(1) Significance:  Does this study address an important problem?  If the aims
of the application are achieved, how will scientific knowledge be advanced? 
What will be the effect of these studies on the concepts or methods that drive
this field?

(2) Approach:  Are the conceptual framework, design, methods, and analyses
adequately developed, well-integrated, and appropriate to the aims of the
project?  Does the applicant acknowledge potential problem areas and consider
alternative tactics?

(3) Innovation Does the project employ novel concepts, approaches or methods? 
Are the aims original and innovative? Does the project challenge existing
paradigms or develop new methodologies or technologies?

(4) Investigator:  Is the investigator appropriately trained and well suited
to carry out this work?  Is the work proposed appropriate to the experience
level of the Principal Investigator and other researchers (if any)?

(5) Environment:  Does the scientific environment in which the work will be
done contribute to the probability of success?  Do the proposed experiments
take advantage of unique features of the scientific environment or employ
useful collaborative arrangements?  Is there evidence of institutional
support?

The initial review group will also examine the provisions for the protection
of human and animal subjects, the safety of the research environment, and
conformance with the NIH Guidelines for the Inclusion of Women and Minorities
as Subjects in Clinical Research.

AWARD CRITERIA

Applications will compete for available funds with all other approved
applications.  The following will be considered in making funding decisions: 
Quality of the proposed project as determined by peer review, availability of
funds, and program priority.

INQUIRIES

Inquiries are encouraged.  The opportunity to clarify any issues or questions
from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Dianne M. Rausch, Ph.D.
Office of AIDS Research
National Institute of Mental Health
6001 Executive Boulevard, Room 6209, MSC 9619
Bethesda, MD  20892-9619
Telephone:  (301) 443-6100
FAX:  (301) 443-9379
Email:  dr89b@nih.gov

Charles W. Sharp,  Ph.D
Division of Basic Research
National Institute on Drug Abuse
6001 Executive Boulevard, Room 4284, MSC 9555
Bethesda, MD  20892-9555
Telephone:  (301) 443-1887
FAX:  (301) 594-6043
Email:  cs107m@nih.gov

A. P. Kerza-Kwiatecki, Ph.D.
Division of Convulsive, Infectious, and Immune Disorders
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard, Room 2117, MSC 9160
Bethesda, MD 20892-9160
Telephone:  (301) 496-1431
FAX:  (301) 402-2060
Email:  ak45w@nih.gov

Direct inquiries regarding fiscal matters to:

Diana S. Trunnell
Grants Management Branch
National Institute of Mental Health
6001 Executive Boulevard, Room 6115, MSC 9605
Bethesda, MD  20892-9605
Telephone:  (301) 443-2805
FAX:  (301) 443-6885
Email:  Diana_Trunnell@nih.gov

Paul Coulis, Ph.D.
Center for AIDS and Other Medical Consequences of Drug Abuse 
National Institute on Drug Abuse
6001 Executive Boulevard, Room 5190, MSC 9593
Bethesda, MD  20892-9593
Telephone:  (301) 443-1801
FAX:  (301) 594-6566
Email:  pc58q@nih.gov

Dianna Jessee
Grants Management Branch
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard, Room 3261, MSC 9190
Bethesda, MD  20892-9190
Telephone:  (301) 496-9231
FAX:  (301) 402-0219
Email:  dj35j@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.242 and 93.282 (NIMH), 93.279 (NIDA), and 93.853 and 93.854 (NINDS). 
Awards are made under authorization of the Public Health Service Act, Title
IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and
285) and administered under PHS grants policies and Federal Regulations 42 CFR
52 and 45 CFR Part 74.  This program is not subject to the intergovernmental
review requirements of Executive Order 12372 or Health Systems Agency review. 
Awards will be administered under PHS grants policy as stated in the NIH
Grants Policy Statement (October 1, 1998).

PHS strongly encourages all grant and contract recipients to provide a smoke-
free workplace and promote the nonuse of all tobacco products.  In addition,
Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain
facilities (or in some cases, any portion of a facility) in which regular or
routine education, library, day care, health care or early childhood
development services are provided to children.  This is consistent with the
PHS mission to protect and advance the physical and mental health of the
American people.


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